Macrolide antibiotics which are effective for gram-positive bacteria, Mycoplasma and Chlamydia are regarded as important antibacterial agents from a clinical viewpoint, since they can be orally administered and show a low toxicity. Among these antibiotics, marketed 16-membered macrolide antibiotics are advantageous in that, for example, the tolerance thereof is scarcely induced and they exert little interaction with other drugs compared with 14-membered ones and scarcely affect the intestinal tract. Thus, they have been widely employed all over the world, mostly, in Asian countries. In particular, miokamycin, which is superior in the dynamics in vivo to natural compounds and has a relieved bitterness [Journal of Antibiotics, 29(5), 536 (1976)]; Japanese Journal of Antibiotics, 35(6), 1462 (1982)] has been frequently employed as a semisynthetic 16-membered macrolide antibiotic for clinical purposes.
In order to improve the antibacterial activity and/or the dynamics in vivo of 16-membered macrolides, a number of derivatives wherein some of the hydroxyl groups thereof are acylated have been synthesized. On the other hand, several groups of workers have already reported the synthesis of 16-membered macrolide derivatives wherein hydroxyl groups in the mycarose moiety are monoalkylated [Chemistry Letters, p. 769 (1977); JP-A-60-58998; and JP-A-62-234093; the term "JP-A" as used herein means an "unexamined published Japanese patent application"].
Miokamycin, which is a newly marketed 16-membered macrolide antibiotic, is superior to midecamycin in infection-protective action in vivo and recovery ratio in urine, but it is not fully satisfactory. Shomura et al. reported that an acyl group at the mycarose moiety of miokamycin is eliminated in vivo and, as a result, the antibacterial activity of this antibiotic is reduced, which is one of factors interfering the embodiment of its excellent dynamics in vivo [Yakugaku Zasshi, 102(8), 781 (1982)]. It is, therefore, required to develop a 16-membered macrolide derivative which remains stable in vivo and scarcely suffers from any decrease in antibacterial activity when metabolized.